Charged molecules over 500 Dalton typically exhibit poor bioavailability. This limits the delivery of many therapeutically active molecules to their intended targets. Polycationic molecules provide important exceptions to this generalization. Modification of Bovine Serum Albumin (BSA) with ethylene diamine produces “cationionized BSA”, a highly effective antigen carrier. Despite its size (over 66,000 Dalton), cationized BSA efficiently enters cells via an unknown path involving adsorptive uptake. More recently, a number of poly-arginine peptides, peptoids, and peptidomimetics, have been found to exhibit highly efficient uptake into a wide range of mammalian cell types. The conjugation of such poly-Arg peptides to large molecules can facilitate the transduction of peptide, protein, and nucleic acid, conjugates into cells. The mechanism responsible for poly-Arg mediated transport is still unclear, but may involve a receptor mediated, non-endocytotic route. Thus, an opportunity exists for exploiting such a poly-arginine peptide-like transduction mechanism for efficient uptake of therapeutically active molecules by eukaryotic cells.
Current technologies exist for producing high uptake forms of lysosomal enzymes that contain mannose-6-phophate or mannose residues, which are recognized by mannose-6-phosphate or mannose receptors. This method allows delivery of enzymes to lysosomes and is currently being used clinically for treating lysosomal storage diseases with some success. Efficient transport across the blood-brain barrier however, has not been achieved and some enzymes are not efficiently modified and delivered in this way. Another approach, which is under development, is the use of guanidinylated peptidic carriers and non-carbohydrate scaffolds.